Diamine derivatives



?atenteci May 15, 1945 mama DERIVATIVES James E. Kirby, Wilmington, Del., and John F.,

Lontz, Gadsden, Ala., assignors to E. I. du Pont de Nemours & Compan corporation of Delaware No Drawing. 'Appllcation October 7, 1942,

3, Wilmington, Del., a

Serial No. 461,166

8 Claims.

This invention relates to new compounds containing at least two nitrogen atoms and more particularly refers to long chain bis-quaternary ammonium compounds and processes for their production and use.

Numerous disinfectant compositions have been described in the scientific literature. As is well known many of these compositions lose a portion or all of their activity in the presence of blood, blood serum and other protein materials. Likewise, a large number of these compounds contain mercury or other heavy metals to which many individuals are sensitive. The foregoing disadvantages in prior art compositions of this type restrict greatly their fields of use.

It is an object of the present invention to produce compounds which overcome the previously mentioned disadvantages and numerous other disadvantages which directly or indirectly result therefrom. A further object is to produce disinfectant compositions which are highly effective in destroying or preventing the growth of bacteria, molds, fungi and related organisms. A still further object is to produce a class of new chemical compounds which in addition to their disinfectant properties are of use for many other purposes in the chemical arts. Additional objects will become apparent from a consideration of the following description and claims.

These objects are attained in accordance with the present invention wherein compounds are produced which conform to the following general formula:

a a R R R N CH=M NR i it wherein R. is a monovalent straight chain alkyl group containing at least ten carbon atoms; R

is a lower molecular weight alkyl group; and X is an anion.

In a more restricted sense this invention is concerned with the production of compounds conforming to the foregoing general formula wherein R is a straight chain alkyl group containing from 10-18 carbon atoms; R is a methyl or ethyl group; and X is an anion of an acid having a dissociation constant greater than 1 x 10*". In

a still more restricted sense this invention is concerned with compounds conforming to the foregoing general .formula wherein R is a straight chain alkyl group containing from 10-18 carbon preferred embodiment this invention pertains to the use of the foregoing compounds in disinfectant compositions.

The compounds embraced herein are bisquaternary ammonium salts in which the nitrogen atoms are separated by a decamethylene chain, and in addition each nitrogen atom carries two alkyl groups having not more than two carbon atoms, one straight chain higher alkyl group of 10-18 carbon atoms, and an anion of an acid having a dissociation constant greater than 1 x 10 Compounds of this type may in accordance with this invention be produced by several methods.

In accordance with one of these methods these compounds may be produced by reacting, for example, one mole of an N,N,N',N-tetraalky1- decamethylenediamine as N,N,N',N'-tertamethyldecamethylenediamine with two moles of a higher alkyl halide such as dodecyl chloride for a period of 24 hours in methanol at C. At the end of this time the methanol is removed by evaporation in the absence of moisture yielding the desired product.

In accordance with a second method these compounds are made by reacting, for example, a decamethylene dihalide such as 1,10-decamethylene dibromide with a tertiary amine such as N-dodecyldimethylamine.

In accordance with a third method these compounds are made by the methylation or ethylation with the corresponding allwl halide or dialkyl sulstandard F. D. A. (Food 8:

utes.

fate of a disecondary amine of the following type: RNHwHz) mNHR.

wherein R. is a straight chain higher alkyl group of 10-18 carbon atoms.

Intermediates used in producing the products a Decamethylene bis (dimethyldecylammonium bromide) A mixture of 11.4 parts of N,N.N.N'-tetramethyldecamethylenediamine and 22.1 parts of n-decyl bromide in 50 parts of methanol is heated in a closed vessel for 24 hours at 100 C. The reaction mixture is cooled and the methanol is removed by evaporation under reduced pressure. The residue is treated with 500 parts of dry ether and is then allowed to stand several days. The solid is removed by filtration, washed with ether and dried in vacuo over phosphorus pentoxide. A quantitative yield of an exceedingly hygroscopic white crystalline solid is obtained. Analysis calcd for CIMH'HNZBI'Z, Br 23.84; found, Br 23.83.

The above compound when tested by the Drug Administration) method for bactericidal activity at dilutions of 1:100,000 kills Staphylococcus aureus in 5 min when the above test is carried out in the presence of whole blood, the killing dilution is found to be 1:5,000 in 5 minutes. This compound shows high bactericidal activity against other organisms; e. g., B. coli and B. typhosis are killed at dilutions of 1:200,000 in 5 minutes. The compound shows bacteriostatic activity against Staphylococcus aureus at dilutions of 1:1,000,000 when tested in broth by the well known standard method. When tested for bacteriostatic action in broth containing 10% blood, the compound is active at dilutions of 1:330,000.

The compound when tested against Staphylococcus aureus by the well known agar cup plate method gives the following results:

Zones of growth inhibition in mm. after 2 days incubation at room temperature Zones of growth inhibition in mm. after 1 week incubation at room temperature In plain agar 11. 7. 0 6. 0 +10% horse serum 8. 0 4. 0 2. 5

In plain agar horse serum The compound shows some protective action for mice against Pneumococcus Type 1. Seven mice were given 0.1 cc. of a 1:200 solution of decamethylene bis (dimethyldecylammonium bromide). by subcutaneous injection following an intraperitoneal injection of Type I Pneumococcus. Of this group, three mice were dead in 24 hours, two died in hours, one died in 48 hours, and one died after 14 days. Control mice given similar injections of Pneumococcus all died within 24 hours.

Decamethylene-bis (dimethyldecylammonium bromide) is active in the presence of saliva, as indicated by the abilty of the compound to kill Staphylococcus aureus at a dilution of 1:1,000 in the presence of saliva in one-half minute,

The compound was found to have a minimum lethal dose (the dose which kills one half of the animals) of 275 mg./kg. when administered subcutaneously to mice. By intraperitoneal injection, the minimum lethal dose was found to be 150 mgjkg.

v Exmm: II

Decamethylene-bis- (dimethyldecillammonium chloride) A mixture consisting of 35.3 parts of decyl chloride, 22.8 parts of N,N,N,N'-tetramethyldecamethylenediamine and parts of methanol is placed in a closed vessel and heated at C. for 64 hours. The mixture is cooled and the methanol is removed by evaporation. The crystalline residue which remains is suspended in dry ether and filtered. The product is dried in vacuo, yielding 40 parts of a white hygroscopic crystalline solid.

The above compound was tested for bactericidal activity by the standard F. D. A. (Food 81 Drug Administration Method) against Staphylococcus aureus at 37 C. in the presence of 10% horse serum. The results are given in the following table: i

. Phenol Dilution control indicates growth.

When tested against Staphylococcus aureu at 37 C. by the standard F. D. A. method without serum present. the results in the following table were obtained:

Dilution 150, 000 175, 000 i-100, 000 l-i50, 000 1-1)0, 000

Cultures:

5 min. 10 min 15 min indicates growth.

Bactericidal titers for this compound against other organisms are given in the following table:

Weakest dilution lethal in water solution Organism min. min. min.

E. em 1-100,000 1-100,000 1-100,000 B. m 1-100,000 1-100,000 1-100,000 Sta ulococcus albm 1-50, 1l00,000 1-100,000 Proteus morga'nil 1-l00,000 ll00,000 1100,000 H. catarrllalis l-200, 1-300, l-300,000 Pneumococcus Type I.. 1-l00,000 1100,000 l-l00.000 Hemolytic streptococcus 1-200,000 1200,000 1200,000 Viridans streptococcus ll00.000 1-100,000 1200,000 Bovine streptococcus 1l00,000 l200.000 1- I000 Bovine hemolytic streptoooccus.. 1-30, l50,000 150,000 Paradysentery 1-50, 150,000 150,000 tery 1-100,000 1-10o,00o 1-100,000 a .albacana 1-100,000 1-100.000 1-ao0,0o0 Trichophuum roaaceum 1-30, 1-30,000 1-50,

Bacteriostatic titers for this compound were determined for other organisms in broth. This test consists in adding to broth a given amount of the test compound followed by inoculation of the broth with the organism. The growth of the bacteria is, then observed for a period of 5 days at 37 C. The highest dilution at which no growth takes place is considered the maximum effective bacteriostatic dilution. The results obtainedare included in the following table:

Weakest dilu- Organlsm tion bacteriostatic Staphylococcus aureus 1-500. 000 Staphylococcus alb'aa 1-500, 000 B. W hosus i-367,000 E.c r i-367,000 Pneumococcus Type I...-.. l667,000 Hemolytic streptococcus... 14,000,000 Viridans streptococcus.... l-l, 330,000 Bovine streptococcus l-l, 330,000 Bovine hemolytic streptococcus. 1-1. 000. 000 N. calarrhalia 15, 000.000 1-250000 1-2, 500,000 1-1, 330,000 1-1,as0,000

This compound was tested for fungistatic properties by the agar plate cup method against Trichophyton rosaceum. In-this method which indicates the penetrating power of the antiseptic agent, the chemical as a dilute water solution is placed in a small depressionin agar containing the organism. The diameter of the area of growth inhibition is then measured in millimeters. The results of these tests are given in the following table.

Zone of growth inhibition in mm. after 14 v days tincuhattion (at room empera urc, 1- Medum lution Plain agar..... 6.0 3.0 +107 horse serum 6.0 2.0 horseserum 5.0 3.0

. Exaurrinlll Decamethylene-bis (dimethyldodecylammoniam chloride) A mixture consisting of 40.8 parts of. dodecyl given in the following table:

Dilution Phenol control 1-20, 000 l-30, 000 l-50, 000 ll- Cultures:

5 min 10 min l5min......

When this compound was tested for bacteriostatic action against Staphylococcus aureus by the agar cup plate method, the following results were obtained as shown in the table below:

Zone 01 growth inhibition in mm. after 14 days incubation at room temperature, Medmm dilution Plain agar 6. 0 4. 0 l. 0 +107 horse serum 5.0 4.0 1.5 +1 ,human blood... 4.0 2.5 0.5 +50% human blood 2. 0 1.0 Trace When this compound was tested for bacteriostatic action against; Staphylococcus aureus in broth the highest dilution in which no growth took place was 1260,000.

EXAMPLE IV Dccamethylene-bis-(dimethyl "Lorol ammonium v chloride) A mixture consisting of 6.8 parts of N,N,N',N'- tetramethyldecamethylenediamine, 13.0 parts of Lorol chloride (the term "Lorol refers to the alkyl radicals derived from the fatty acids of coconut oil, containing from 8 to 18. carbon atoms) and 25 parts of methanol is heated in a closed vessel at 100 C. for 64 hours. The mixture is then cooled and the methanol removed by evap oration. The residue is suspended in dry ether and filtered. The product is dried in vacuo, yielding 5.1' parts of a white. hygroscopic crystalline solid. properties. Analysis found: Cl 11.43. I

This compound was tested for. bactericidal activity by. the standard F. D..A. method against It, likewise, has excellent disinfectant Staphylococcus aureus at 37 C. .The results are given inthe following table: I

" Dilution 253,2

Cultures: I p

5min.

When this compound was tested for bacteriostatic action against Staphylococcus aureus by the agar cup plate method the results in the fol- When tested for bacteriostatic action the highest dilution in which no growth was obtained was 1-260,000.

It is to be understood that the foregoing examples are illustrative merely of a few of the many modifications to which the present invention is susceptible. They may be varied widely with respect to the individual reactants, the amounts thereof and the conditions of reaction without departing from the scope hereof.

As previously mentioned, compounds coming within the scope of this invention may be represented by the following general formula:

R a n R R NQCH=M NR i x wherein R is a monovalent straight chain alkyl group containing at least ten carbon atoms: R is a lower molecular weight alkyl group; and X is an anion.

In the above formula R. i preferably a higher straight chain alkyl group of 10-18 carbon atoms: R is a methyl or ethyl group; and X is an anion of an acid having a dissociation constant greater than 1X For optimum results over a. wide range of conditions the monovalent straight chain alkyl group (R) attached to each nitrogen atom in these compounds contains from -18 carbon atoms. Radicals conforming to this requirement are decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl. hexadecyl, heptadecyl or octadecyl groups. Of these groups, decyl and dodecyl represent the preferred types. The mixture obtained when R represents the alkyl groups of Lorol" is also a preferred type. Lorol is the mixture of long chain alcohols formed by the carboxylic reduction of coconut oil fatty acids.

, The group previously represented by R is advisably methyl or ethyl, but is preferably the former.

The anion previously represented by X may be the anion of any acid of dissociation constant greater than l 10", such as carbonic, acetic, citric, tartaric, lactic, boric or propionic acid. However, the preferred anions are those of the strong mineral acids, having a dissociation constant greater than 1X 10. such as sulfuric, phosphoric, hydrochloric, hydriodic or hydrobromic. Of this roup of strong acids, hydrochloric and hydrobromic represent the preferred members.

As stated previously, these products may be prepared by any of several methods. For example, a decamethylene dihalide such as decamethylene dichloride or decamethylene dibromide may be reacted with a tertiary amine of the following general formula:

where R and B have the same significance as R. and R in the preceding general formula.

The reaction may be formulated as follows:

R a /n' a a' o1(om)..o1+2r I-a=av(cmn N-a The preferred method of preparation involves the reaction of an alkyl halide such as, for example, decyl chloride decyl bromide, dodecyl chloride or dodecyl bromide with an N.N,N',N'-tetramethylor an N,N,N',N'-tetraethyldecamethylene diamine. This reaction proceeds as follows:

A third method of preparation involves the methylation or ethylation of a disecondsry amine of the following type:

where R is a straight chain higher alkyl group of 10-18 carbon atoms. Dialkyl sulfates (dimethyl sulfate or diethyl sulfate) or alkyl halides (methyl chloride) are employed as the alkylating agent. The reaction may be formulated as follows:

a R a a R-NH-(CHz)IaNHR+4RX=R N- (CHs)" N The reactions involved in these methods of preparation are very similar in that they are all reactions of a hydrocarbon halide with an amine. They may be carried out either in the presence or in the absence of a solvent at temperatures between 75 and 150 C. The reaction may take place at atmospheric, superstmospheric or subatmospheric pressure. The preferred conditions for carrying out the reaction are those using methanol as a solvent at a temperature of loo- C. and sufficient pressure above atmospheric to prevent the loss of methanol by evaporation The products of this invention may beemployed as bactericides or fungicides or as bacteriostatic agents. They are most advantageously used in solution in water or in alcohol. The compounds may be mixed with other bactericidally active ingredients such as phenolic bactericides of the type of phenol, cresol and hexylresorcinol, or with mercurial bacterlcldes such as Metaphen. The bis-quaternary compounds may also be diluted with inert solid ingredients such as tale. The products are useful in the control of harmful bacteria such as Staphylococcus, Pneumococcus, Streptococcus, Bacillus typhosis, and the like. The compounds are also useful as agents for the control of other harmful single celled organisms such as amoeba. Fungi and molds such as the various lumber molds are likewise controlled by these products.

In addition to the foregoing uses these products are also capable of use as surface-active agents either alone, in admixture with one another and/or in admixture with the numerous prior art agents which possess surface activity. Likewise, they may be employed as intermediates in the synthesis of many other organic chemical compounds.

As many widely dliferent embodiment of this invention maybe made without departing from the spirit and scope thereof, it is to be understood that the invention is not limited to the specific embodiments thereof except as defined.

in the appended claims.

We claim:

1. Monomeric bis quaternary ammonium salts in which the nitrogen atoms are separated by a decamethylene chain, and in addition each nitrogen atom carries two alkyl groups of lower molecular weight, a straight chain alkyl group of at least ten carbon atoms, and an anion.

2. Monomeric bis quaternary ammonium salts in which the nitrogen atoms are separated by a decamethylene chain, and in addition each nitrogen atom carries two alkyl groups containing less than three carbon atoms in each group, a straight chain alkyl group containing from ten to eighteen carbon atoms, and an anion of an acid having a dissociation constant greater than 1x10-".

3. Monomeric bis quaternary ammonium salts in which the nitrogen atoms are separated by a decamethylene chain, and in addition each nitrogen atom carries two methyl groups. a

straight chain alkyl group containing from ten to eighteen carbon atoms, and an anion of an acidol aving a dissociation constant greater than 1x 4. Monomeric decamethylene-bis-(dimethyldecyl ammonium chloride).

5. Monomeric decamethylene-bis-) dimethyidodecyl ammonium chloride).

6. Crystalline monomeric materials comprising bis-quaternary ammonium salts in which the nitrogen atoms are separated by a decamethylene chain, and in addition each nitrogen atom carries two methyl groups, a straight chain alkyl group containing from ten to eighteen carbon atoms, and a middle halogen.

'7. Crystalline monomeric materials comprising bis-quatemary ammonium salts in whichthe nitrogen atoms are separated by a decamethylene chain, and in addition each nitrogen atom carries two methyl groups, a straight chain alkyl group containing from ten to twelve carbon atoms, and a middle halogen.

8. Monomeric decamethylene-bis-(dimethyldecylammonium bromide).

JAMES E. KIRBY. JOHN F. LON'I'Z. 

